Submissions for variant NM_000088.4(COL1A1):c.4321G>T (p.Asp1441Tyr)

dbSNP: rs72656351

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001225554	SCV001397837	pathogenic	Osteogenesis imperfecta type I	2019-08-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp1441 amino acid residue in COL1A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25146735, 19199251). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect COL1A1 protein function (PMID:11826020). This variant has been observed in individual(s) with osteogenesis imperfecta (PMID: 11826020, Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with tyrosine at codon 1441 of the COL1A1 protein (p.Asp1441Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine.
PreventionGenetics, part of Exact Sciences	RCV003405411	SCV004115747	pathogenic	COL1A1-related condition	2022-12-04	criteria provided, single submitter	clinical testing	The COL1A1 c.4321G>T variant is predicted to result in the amino acid substitution p.Asp1441Tyr. This variant resides in the carboxyl-terminal propeptide of the proa1(I) chain of type I collagen. This variant has been reported to have arisen de novo in an individual with osteogenesis imperfecta II with features of dense bone disease (Pace et al 2002. PubMed ID: 11826020). Functional studies have shown that this variant causes impaired assembly of type I procollagen (Pace et al 2002. PubMed ID: 11826020; Barnes AM et al 2019. PubMed ID: 31055083). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. An alternative substitution affecting the same amino acid (p.Asp1441His) has also been reported in association with osteogenesis imperfecta (Human Gene Mutation Database; http://www.hgmd.cf.ac.uk/). This variant is interpreted as pathogenic.