ClinVar Genomic variation as it relates to human health

The c.632A>G (p.Asp211Gly) missense variant in the HYLS1 gene has been previously reported in 24 affected individuals with autosomal recessive Hydrolethalus syndrome from 16 families in Finland; this variant was shown to co-segregate with disease in these families (Mee et al., 2005). The residue encoded by this variant is positioned at a protease cleavage site, which is lost upon substitution to glycine (Paetau et al., 2008). Functional studies show this variant affects the subcellular localization, sequestering the protein primarily to the nucleus as opposed to the cytoplasm (Mee et al., 2005). This c.632A>G has been reported at low frequency in the three control population databases (Exome Sequencing Project [ESP] , 1000 Genomes, and ExAC). Multiple lines of computational evidence suggest a deleterious effect. Therefore, this collective evidence supports the classification of the c.632A>G (p.Asp211Gly) as a recessive Pathogenic variant for Hydrolethalus syndrome.

NM_001134793.1(HYLS1):c.632A>G(D211G) is classified as pathogenic in the context of hydrolethalus syndrome. Sources cited for classification include the following: PMID 15843405, 18648327, 19400947 and 19656802. Classification of NM_001134793.1(HYLS1):c.632A>G(D211G) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Published functional studies demonstrate a damaging effect on activation of Hedgehog signaling (Chen et al., 2021); This variant is associated with the following publications: (PMID: 32371413, 34212369, 31589614, 19656802, 35611473, 15843405, 2074561, Morgan[Computational]2017, 34831381, 18648327, 19400947, 34162535)

[ACMG/AMP: PS3, PM1, PS4_Moderate, PP1, PP3, PP5] This alteration is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], has previously been observed in multiple unrelated patients with the same phenotype [PS4_Moderate], has been shown to cosegregate with disease in multiple affected family members [PP1], is predicted to be damaging by multiple functional prediction tools [PP3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 211 of the HYLS1 protein (p.Asp211Gly). This variant is present in population databases (rs104894232, gnomAD 1.0%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with hydrolethalus syndrome (PMID: 15843405, 18648327). It is commonly reported in individuals of Finnish ancestry (PMID: 15843405, 18648327). ClinVar contains an entry for this variant (Variation ID: 1143). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects HYLS1 function (PMID: 15843405). For these reasons, this variant has been classified as Pathogenic.

NM_145014.2:c.632A>G in the HYLS1 gene has an allele frequency of 0.01 in European (Finnish) subpopulation in the gnomAD database. The p.Asp211Gly (NM_145014.2:c.632A>G) variant has been observed in individuals with hydrolethalus syndrome and it has been reported to be a founder mutation in the Finnish population (PMID: 15843405; 18648327). Experimental studies have shown that this missense change causes mislocalization of the HYLS1 protein to the nucleus (PMID: 15843405). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS4; PS3.

The HYLS1 p.D211G variant is reported to be a Finnish founder mutation and has been reported as a homozygous variant in 41 Finnish cases of hydrolethalus syndrome (HLS) (Mee_2005_PMID:15843405; Paetau_2008_PMID:18648327). The variant was identified in dbSNP (ID: rs104894232) and ClinVar (classified as pathogenic by Invitae, Knight Diagnostic Laboratories, Illumina and BGI Genomics). The variant was identified in control databases in 335 of 282870 chromosomes at a frequency of 0.001184 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 241 of 25120 chromosomes (freq: 0.009594), Other in 12 of 7228 chromosomes (freq: 0.00166), European (non-Finnish) in 79 of 129190 chromosomes (freq: 0.000612), Ashkenazi Jewish in 1 of 10368 chromosomes (freq: 0.000096) and African in 2 of 24964 chromosomes (freq: 0.00008), but was not observed in the Latino, East Asian, or South Asian populations. The p.D211 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. However, functional analysis has demonstrated that the p.D211G variant causes mislocalization of the HYLS1 protein to the nucleaus instead of the cytoplasm (Mee_2005_PMID:15843405). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.