ClinVar Genomic variation as it relates to human health

The variant c.1955A>C (p.Lys652Thr), also known as p.Lys650Thr, is reported as pathogenic for FGFR3 related disorders in ClinVar (Variation ID: 65855) There is no information on frequency in gnomAD, 1000 Genomes or NHLI Exome Sequencing Project (ESP). The nucleotide position is moderately conserved across 35 mammalian species (GERP RS: 3.12). The variant has been firstly reported by Berk et al. in a familial case of acanthosis nigricans associated with slightly short stature, without other anomalies (Berk et al., 2007, PMID: 17875876). Later, the same mutation has been described in a familial case of hypochondroplasia (HCH) and acanthosis nigricans (AN) by Castro-Feijo´o et al. (2008). Cossiez Cacard et al. (2016) found this mutation in a family with AN associated with hypochondroplasia. Codon 650 of FGFR3 is located in the tyrosine kinase domain II. Mutations of this codon have been reported in skeletal disorders including hypochondroplasia (p.Lys650Asn and p.Lys650Gln), SADDAN syndrome (p.Lys650Met), thanatophoric dysplasia type I (p.Lys650Met), and thanatophoric dysplasia type II (p.Lys650Glu) (Berk et al., 2007, PMID: 17875876).

The FGFR3 c.1949A>C variant is predicted to result in the amino acid substitution p.Lys650Thr. This variant was repeatedly reported to be pathogenic for acanthosis nigricans with or without hypochondroplasia (see examples: Berk et al. 2007. PubMed ID: 17875876; Castro-Feijóo et al. 2008. PubMed ID: 18583390; Hirai et al. 2017. PubMed ID: 29026271; Fu et al. 2019. PubMed ID: 30635042). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.

Published functional studies demonstrate the K650T variant significantly increased FGFR3 tyrosine kinase activation as compared to wildtype (PMID: 11055896); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28181399, 25809207, 28620983, 26818779, 17875876, 29068064, 31036092, 29026271, 34358384, 11055896, 18583390, 30635042)

This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 650 of the FGFR3 protein (p.Lys650Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with acanthosis nigricans (PMID: 17875876, 18583390, 25809207, 26818779). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65855). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FGFR3 protein function. Experimental studies have shown that this missense change affects FGFR3 function (PMID: 11055896). For these reasons, this variant has been classified as Pathogenic.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with autosomal dominant skeletal dysplasias (OMIM). Additionally, autosomal recessive and dominant CATSHL syndrome (MIM#610474), is suspected to be due to variants with a loss of function, and dominant negative mechanism, respectively (PMIDs: 25614871, 24864036). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Individuals with Muenke syndrome have been shown to inherit pathogenic variants from an asymptomatic parent (PMIDs: 26740388, 18000976). (I) 0115 - Variants in this gene are known to have variable expressivity. There is a wide range of clinical symptoms with variable expressivity in LADD and Muenke syndrome patients, even within the same family (PMIDs: 26740388, 16501574). (I) 0200 - Variant is predicted to result in a missense amino acid change from lysine to threonine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated protein tyrosine and serine/threonine kinase domain (DECIPHER). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Four alternative amino acid changes at this residue have been classified as pathogenic/likely pathogenic by multiple clinical laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and observed in multiple families with acanthosis nigricans with or without hypochondroplasia in the literature (PMID: 30635042). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Greater likelihood of developing acanthosis nigricans [Berk et al 2010, Blomberg et al 2010]