Submissions for variant NM_005219.5(DIAPH1):c.2224C>G (p.Pro742Ala)

gnomAD frequency: 0.00036  dbSNP: rs199749212

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000652774	SCV000774645	uncertain significance	Autosomal dominant nonsyndromic hearing loss 1; Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 742 of the DIAPH1 protein (p.Pro742Ala). This variant is present in population databases (rs199749212, gnomAD 0.05%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with DIAPH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 542364). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV000652774	SCV000897208	uncertain significance	Autosomal dominant nonsyndromic hearing loss 1; Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825744	SCV000967203	likely benign	not specified	2018-12-23	criteria provided, single submitter	clinical testing	The p.Pro742Ala variant in DIAPH1 is classified as likely benign because it has been identified in 0.05% (63/128264) of European chromosomes including 1 homozyg ote by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BS1 .
Illumina Laboratory Services, Illumina	RCV001155495	SCV001316923	uncertain significance	Autosomal dominant nonsyndromic hearing loss 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV001592824	SCV001826417	uncertain significance	not provided	2024-03-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
PreventionGenetics, part of Exact Sciences	RCV004752983	SCV005360580	uncertain significance	DIAPH1-related disorder	2024-07-30	no assertion criteria provided	clinical testing	The DIAPH1 c.2224C>G variant is predicted to result in the amino acid substitution p.Pro742Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.049% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.